Conjugation pathways in liver disease.

1. The activities of microsomal glucuronyltransferase and thiomethyltransferase, and those of cytosolic sulphotransferase, acetyltransferase, glutathione transferase and thiomethyltransferase were measured in abnormal (cirrhosis and chronic hepatitis) and normal livers. 2. Glucuronyltransferase and sulphotransferase were investigated with 2-naphthol and ethinyloestradiol as substrates. p-Aminobenzoic acid, benzo(a)pyrene-4,5-epoxide and 2-mercaptoethanol were the substrates of acetyltransferase, glutathione transferase and thiomethyltransferase, respectively. 3. Enzyme activities are expressed as nmol min-1 incubation mg-1 protein and the averages (+/- s.d.) are given. With 2-naphthol as substrate, the glucuronyltransferase activity was 6.55 +/- 4.10 (abnormal liver, n = 33) and 7.81 +/- 4.02 (normal liver, n = 26) (NS); whereas sulphotransferase activity was 0.28 +/- 0.18 (abnormal liver, n = 35) and 0.68 +/- 0.43 (normal liver, n = 26) (P less than 0.01). Glucuronyltransferase activity towards ethinyloestradiol was 102.5 +/- 56.9 (abnormal liver, n = 30) and 107 +/- 59.9 (normal liver, n = 26) (NS), whereas sulphotransferase activity was 57.2 +/- 36.0 (abnormal liver, n = 35) and 122 +/- 67.6 (normal liver, n = 28) (P less than 0.01). Acetyltransferase activity was 0.84 +/- 0.83 (abnormal liver, n = 35) and 3.84 +/- 1.65 (normal liver, n = 26) (P less than 0.01). Glutathione transferase activity was 0.83 +/- 0.68 (abnormal liver, n = 35) and 2.90 +/- 1.59 (normal liver, n = 25) (P less than 0.01) and thiomethyltransferase activity was 1.00 +/- 0.69 (abnormal liver, n = 34) and 3.99 +/- 1.49 (normal liver, n = 25) (P less than 0.01). 4. Liver disease lowers the activities towards the substrates studied of sulphotransferase, acetyltransferase, glutathionetransferase and thiomethyltransferase but not that of glucuronyltransferase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epileptic patients refractory to drug therapy

We compared two groups of patients with idiopathic epilepsy, 41 patients whose seizure frequency was not controlled by adequate therapy and 39 patients in good seizure control, in respect of hematology, kidney and liver function tests, serum IgG, IgA and IgM concentrations and drug concentrations. The only difference that emerged were in the serum immunoglobulins, which were raised in the drug refractory group, significantly (p less than 0.01) so in the case of IgG. Failure of seizure control did not depend on inadequacy of drug dose or of blood concentration. Although the serum Ig changes do not warrant the assumption of an immunological origin for drug resistance, they do suggest a useful research line.     

Plasma protein binding of furosemide in the elderly

Summary The protein binding of furosemide was investigated in plasma from 22 old and 11 young subjects by equilibrium dialysis. The unbound fraction of furosemide was 3.16% in plasma from the elderly and 1.71% in plasma from the young. A significant correlation was found between the unbound fraction of furosemide and the plasma concentration of albumin. The average number of binding sites was 3.8 (elderly) and 2.7 (young) 10^–6 mol/g albumin. The average association constant (K) was 4.3 (elderly) and 4.2 (young) 10⁵ M^–1. By increasing the concentration of furosemide up to 200 µg/ml buffer the unbound fraction of the drug rose to 5.2% (elderly) and 3.5% (young).     

Distribution of 2-naphthol sulphotransferase and its endogenous substrate adenosine 3′-phosphate 5′-phosphosulphate in human tissues

The activity of sulphotransferase towards 2-naphthol and the concentration of its endogenous substrate, adenosine 3'-phosphate 5'-phosphosulphate (PAPS), have been measured in five specimens of human liver, lung, and kidney, and the mucosa from the ileum and the ascending, descending and sigmoid colon. The activity of 2-naphthol sulphotransferase (mean nmol.min-1.mg-1 protein) was 1.82 (liver); 0.034 (kidney); 0.19 (lung); 0.64 (ileum); 0.47 (ascending colon); 0.50 (descending colon); 0.40 (sigmoid colon). The concentration of PAPS (mean nmol.g-1 wet tissue) was 22.6 (liver); 4.8 (kidney); 4.3 (lung); 12.8 (ileum); 8.1 (ascending colon); 7.5 (descending colon); 6.2 (sigmoid colon). The concentration of PAPS and the activity of 2-naphthol sulphotransferase were higher in the liver than in the extrahepatic tissues. There was significant difference between ileum and ascending colon, both the activity of sulphotransferase and the concentration of PAPS being higher in the former. 2-Naphthol sulphotransferase activity and the concentration of PAPS have consistent distribution patterns. Differences between the tissues studied were more marked for sulphotransferase than for its endogenous substrate.     

Morphine and methadone impact on human phagocytic physiology

Human subjects submitted to treatment with morphine show a severe depression of phagocytosis, killing properties and superoxide production both of their polymorphonuclear leukocytes and monocytes. Polymorphonuclear leukocyte adherence, chemotaxis, random migration, myeloperoxidase content, lysozyme content and lymphocyte Rosette E formation were poorly influenced. Methadone-treated subjects show a similar effect at phagocytic level but far less evident. These results confirm those previously found in animals and reinforce the evidence of a depressive role of morphine on phagocytic physiology.     

Interethnic and interindividual variabilities of platelet sulfotransferases activity in Italians and Finns

Objective: The aim of this investigation was to see whether there was interethnic variability in the platelet activities of catechol- and phenol sulfotransferases in Italians and Finns. Methods: The activities of catechol- and phenol sulfotransferases were measured in platelets obtained from 103 Italian and 74 Finnish individuals. Blood donors were obtained from healthy volunteers free from drugs and without apparent disease. The activities of catechol- and phenol sulfotransferases were measured with 60 μM dopamine and 4 μM 4-nitrophenol as substrates, respectively Results: The activity of catechol sulfotransferase was not gender dependent and the median estimates (pmol/min/mg) were 9.10 in Italians and 6.37 in Finns (P = 0.0018). The activity of phenol sulfotransferase activity was gender dependent in Finns but not in Italians. The median estimates (pmol/min/mg) were 3.81 in Finnish men and 1.18 in Finnish women (P = 0.0007). In Italian men and women, the median estimates (pmol/min/mg) of phenol sulfotransferase activity were 1.25 and 1.24, respectively (NS). Conclusion: This study shows that platelet catechol sulfotransferase activity is greater in Italians than Finns and that the activity of phenol sulfotransferase is gender regulated in Finns but not in Italians. Thus, interethnic differences exist in platelet sulfotransferases between Italians and Finns. Received: 16 April 1999 / Accepted in revised form: 20 August 1999     

Determination of opiates and cocaine in hair as trimethylsilyl derivatives using gas chromatography-tandem mass spectrometry.

An analytical method for the determination of heroin, 6-monoacetylmorphine, morphine, codeine, cocaine, benzoylecgonine, and cocaethylene in human hair using gas chromatography-tandem mass spectrometry is presented. The analytes were extracted from finely cut hair with methanol at 56 degrees C for 18 h in the presence of nalorphine as the internal standard. After the incubation, methanol was evaporated to dryness, and all the analytes, except heroin, cocaine, and cocaethylene, were converted to their trimethylsilyl derivatives. The reaction products were identified and quantitated using product ions formed from the parent ions by collision-induced dissociation in the ion-trap mass spectrometer. This method provided excellent sensitivity and specificity for analytes at the concentrations usually found in the keratin matrix.     

Synthesis and pharmacological activity and some derivatives of 1-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one.

4-N-Alkylamino derivatives and corresponding ammonium quaternary salts of tetrahydro-1,4-benzodiazepin-5-one were synthesized and evaluated for psychotropic activity in mice by ip via. This study was also extended to some nitro and amino derivatives of tetrahydro-1,4-benzodiazepin-5-one. Compounds were devoid of tranquilizing activity and in comparison with two classical benzodiazepines, chlordiazepoxide and diazepam, they showed high toxicity and little or no effect on motor coordination, motor activity, and maximal electroshock. On some "in vitro" tests the compounds exhibited pharmacological properties when they were used at high concentrations.